The proposed research project will focus on the design, synthesis, evaluation, and development of targeted desferrithiocin analogues for the treatment of iron overload. Physicians have a pressing clinical need for new, more effective iron-chelating agents which selectively remove iron from the liver, heart, and pancreas, the organs at greatest risk of iron-induced injury in patients with thalassemia major, sickle cell disease, hereditary hemochromatosis and other forms of iron overload. Desferrithiocin (DFT), a natural product iron chelator (siderophore) isolated from Streptomyces antibioticus, is one of the most orally effective iron chelating agents yet identified but renal toxicity precludes its clinical use. Our systematic structure-activity studies have allowed the design and synthesis of analogues and derivatives, which retain the exceptional iron-chelating activity of DFT without adverse effects on the kidneys or other organs. Our lead compound, the orally active DFT analogue (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT (28)], which is nearly three times as effective as sc DFO in the C. apella primate model, has been licensed to a commercial sponsor and currently is in Phase I/II clinical trials. We now hypothesize that the DFT platform can be structurally programmed to target delivery to organs at greatest risk of iron induced injury and to further enhance iron clearance. To test these hypotheses, our research plan has three specific aims: Aim 1: to design and synthesize partition-variant desferrithiocin analogues with enhanced access to organs vulnerable to iron-induced injury (eg, liver, heart, pancreas) and/or increased iron clearing efficiency; Aim 2: to design and synthesize polyamine-vectored desferrithiocin analogues that use the polyamine transport apparatus to gain entry into cells; and Aim 3: to assess these new desferrithiocin analogues in physiochemical, cellular and animal models to identify safe and effective compounds for GLP preclinical evaluation in preparation for human studies. The development of safe, effective, and well-tolerated iron-chelating agents based on DFT would be a major advance in the treatment of iron overload that would greatly enhance both the quality and length of life of affected patients in the United States and worldwide.